Salts and Solid Forms of Kinase Inhibitors

Abstract

Disclosed are various salt and free base solid forms of Compound (I) represented by the formula: JPEG2024509276000081.jpg7283 Pharmaceutical compositions containing same, methods of using same to treat disorders and conditions associated with oncogenic KIT and PDGFRA mutations, and methods for making salt forms of Compound (I) and crystalline forms thereof are also disclosed.

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 159,107, filed March 10, 2021, and U.S. Provisional Application No. 63 / 208,641, filed June 9, 2021, the entire contents of which are incorporated herein by reference.

[0002] The enzyme KIT (also known as CD117) is a receptor tyrosine kinase expressed in a wide variety of cell types. The KIT receptor protein belongs to the class III receptor tyrosine kinase (RTK) family, which also includes the structurally related proteins PDGFRα (platelet-derived growth factor receptor A), PDGFRβ, FLT3 (FMS-like tyrosine kinase 3), and CSF1R (colony-stimulating factor 1 receptor). The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF). Normally, SCF binds to KIT and activates it by inducing dimerization, autophosphorylation, and initiation of downstream signaling. However, in some tumor types, somatic activating mutations in KIT drive ligand-independent constitutive activity.

[0003] KIT mutations commonly occur in the DNA encoding the juxtamembrane domain (exon 11). KIT mutations also occur less frequently in exons 7, 8, 9, 13, 14, 17, and 18. Mutations render KIT function independent of activation by SCF, leading to rapid cell division rates and possibly genomic instability. Mutant KIT has been implicated in the pathogenesis of several disorders and conditions, such as mastocytosis, gastrointestinal stromal tumors (GISTs), acute myeloid leukemia (AML), melanoma, and seminoma.

[0004] The structurally related platelet-derived growth factor receptor (PDGFR) is a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor (PDGF) family. The α and β subunits of PDGF regulate cell proliferation, differentiation, proliferation, and development. Mutations (e.g., mutations) in the α and β subunits of PDGF are associated with many diseases, including some cancers. For example, the D842V mutation in PDGFRα exon 18 has been found in a unique subset of gastric gastrointestinal stromal tumors (GISTs), typically from the stomach. The D842V mutation is also associated with tyrosine kinase inhibitor resistance. Furthermore, other exon 18 mutations, such as PDGFRα D842I and PDGFRα D842Y, are associated with ligand-independent constitutive activation of PDGFRα. In GISTs, gain-of-function mutations (e.g., PDGFRα D842I, D842V, and D842Y) that confer ligand-independent constitutive activation of PDGFRα signaling have been identified as disease drivers.

[0005] U.S. Patent No. 10,829,493 (the entire teachings of which are incorporated herein by reference) discloses potent and highly selective inhibitors of KIT and / or PDGFRα exon 18 mutant proteins, including exon 17 mutant proteins. The structure of one of the inhibitors disclosed in U.S. Patent No. 10,829,493, referred to herein as "Compound (I)," is shown below. [ka]

[0006] Compound (I) is a potent and selective small molecule inhibitor of the KIT exon 17 mutant enzyme, i.e., KIT D816V. Its efficacy has been demonstrated in vitro in both biochemical (dissociation constant, Kd = 0.24 nM) and cellular (half maximal inhibitory concentration, [IC50] = 4.3 nM) settings. Compound (I) is highly selective for KIT D816V when compared against other kinases, transmembrane or soluble receptors, ion channels, transporters, and other enzymes. Compound (I) has limited brain penetration potential.

[0007] The successful development of a pharmaceutically active agent, such as Compound (I), typically requires the identification of a solid form that has properties that allow for easy isolation and purification after synthesis, are amenable to large-scale manufacturing, can be stored for extended periods with minimal water absorption, degradation, or conversion to other solid forms, is suitable for formulation, and is readily absorbed (e.g., is soluble in water and gastric fluids) after administration to a subject. Summary of the Invention

[0008] It is now known that the free base of Compound (I) has multiple crystalline forms that can interconvert into each other due to differing amounts of water present in the crystal lattice. As a result, the preparation of stable crystalline forms of the free base of Compound (I) has proven difficult to reproduce on a production scale.

[0009] It has also now been discovered that the 1:1 phosphate, 2:1 besylate, 1:1 benzoate, and 1:1 sulfate salts can be crystallized under well-defined conditions to yield non-hygroscopic crystalline forms. These four salts exhibit good thermal behavior with high onset melting points, making them suitable for large-scale synthesis. Minimal mass loss was observed during thermogravimetric analysis. The salts disclosed herein also exhibited similar solubilities in simulated fluids and water at 37°C.

[0010] Furthermore, the 1:1 phosphate salt maintained a purity of over 98%. Among the crystalline forms of the 1:1 phosphate salt, anhydrous crystalline Form A of the phosphate salt was found to be the most stable form. Form A was highly crystalline with a melting onset of 199.7 °C. Form A exhibited low residual solvent (0.45 wt%) and good solubility in simulated fluids and water. Form A also exhibited low solubility in selected organic solvents and solvent mixtures, but was soluble in high-boiling solvents such as dimethylacetamide (DMAc), n-methylpyrrolidone (NMP), and dimethyl sulfoxide (DMSO), as well as in aqueous / organic mixtures (especially with tetrahydrofuran (THF)). Form A was obtained from different crystallization experiments in slurries with alcohol, acetate, acetone, methyl ethyl ketone (MEK), trifluoroethanol (TFE), dioxane, chlorobenzene, chloroform, anisole, and in many aqueous / organic mixtures. Crystallization using 2-MeTHF was advantageous in that it provided crystalline Compound (I) phosphate Form A with robust control of residual solvent.

[0011] The notation "1:1" refers to the molar ratio between Compound (I) and an acid (e.g., sulfuric acid, phosphoric acid, or benzoic acid), and the notation "2:1" refers to the molar ratio between Compound (I) and an acid (e.g., benzenesulfonic acid).

[0012] In one aspect, the present disclosure provides a phosphate salt of Compound (I), wherein the molar ratio between Compound (I) and phosphoric acid is 1:1.

[0013] In another aspect, the present disclosure provides a besylate salt of Compound (I), wherein the molar ratio between Compound (I) and benzenesulfonic acid is 2:1.

[0014] In yet another aspect, the present disclosure provides a sulfate salt of Compound (I), wherein the molar ratio between Compound (I) and sulfuric acid is 1:1.

[0015] In yet another aspect, the present disclosure provides a benzoate salt of Compound (I), wherein the molar ratio between Compound (I) and benzoic acid is 1:1.

[0016] In another aspect, the present disclosure provides a pharmaceutical composition comprising a salt or free base of Compound (I) disclosed herein (including both amorphous and crystalline forms) and a pharmaceutically acceptable carrier or diluent.

[0017] The present disclosure provides methods for treating disorders and conditions associated with oncogenic KIT and PDGFRA mutations, the methods comprising administering to a patient in need thereof a salt or free base (including both amorphous and crystalline forms) of Compound (I) disclosed herein, or its corresponding pharmaceutical composition.

[0018] The present disclosure provides a method of treating a disease or condition in a patient in need thereof, the method comprising administering to a patient in need thereof a salt or free base of Compound (I) disclosed herein (including both amorphous and crystalline forms), or its corresponding pharmaceutical composition, wherein the disease or condition is selected from systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intracranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer. In one embodiment, the disease or condition is selected from systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, and chronic myelomonocytic leukemia. In one embodiment, the disease or condition is systemic mastocytosis. In one embodiment, the systemic mastocytosis is selected from indolent systemic mastocytosis and smoldering systemic mastocytosis.

[0019] The present disclosure also provides the use of the salt or free base of Compound (I) of the present disclosure or its pharmaceutical composition comprising it for the treatment of any of the diseases listed in the previous paragraph.In one embodiment, the salt or free base of the present disclosure or its pharmaceutical composition comprising it is provided for use in any of the methods of the present disclosure described herein.In another embodiment, the use of the salt or free base of the present disclosure or its pharmaceutical composition comprising it for the manufacture of a medicament for any of the methods of the present disclosure described is provided. [Brief explanation of the drawings]

[0020] [Figure 1A] 1 shows the X-ray powder diffraction (XRPD) pattern of Form A of the phosphate salt of Compound (I), wherein the molar ratio between Compound (I) and phosphoric acid is 1:1. [Figure 1B] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) (5 mW) thermograms of Form A of the phosphate salt of Compound (I), where the molar ratio between Compound (I) and phosphoric acid is 1:1. [Figure 1C] 1 shows a differential scanning calorimetry (DSC) (10 mW) thermogram of Form A of the phosphate salt of Compound (I), where the molar ratio between Compound (I) and phosphoric acid is 1:1. [Figure 2A] 1 shows the X-ray powder diffraction (XRPD) pattern of Form G of the phosphate salt of Compound (I), wherein the molar ratio between Compound (I) and phosphoric acid is 1:1. [Figure 2B] (Zoomed y-axis) shows the X-ray powder diffraction (XRPD) pattern of Form G of the phosphate salt of Compound (I), where the molar ratio between Compound (I) and phosphoric acid is 1:1. [Figure 2C] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form G of the phosphate salt of Compound (I), where the molar ratio between Compound (I) and phosphoric acid is 1:1. [Figure 2D] 1 shows a differential scanning calorimetry (DSC) thermogram of Form G of the phosphate salt of Compound (I), where the molar ratio between Compound (I) and phosphoric acid is 1:1. [Figure 3] 1 shows the X-ray powder diffraction (XRPD) pattern of Form O of the phosphate salt of Compound (I), where the molar ratio between Compound (I) and phosphoric acid is 1:1. [Figure 4A] 1 shows the X-ray powder diffraction (XRPD) pattern of Form 1-A of the besylate salt of Compound (I), wherein the molar ratio between Compound (I) and benzenesulfonic acid is 1:2. [Figure 4B] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 1-A of the besylate salt of Compound (I), where the molar ratio between Compound (I) and benzenesulfonic acid is 1:2. [Figure 4C] 1 shows a differential scanning calorimetry (DSC) thermogram of Form 1-A of the besylate salt of Compound (I), where the molar ratio between Compound (I) and benzenesulfonic acid is 1:2. [Figure 5] 1 shows the X-ray powder diffraction (XRPD) pattern of Form 1-B of the besylate salt of Compound (I), where the molar ratio between Compound (I) and benzenesulfonic acid is 1:2. [Figure 6A] 1 shows the X-ray powder diffraction (XRPD) pattern of Form 2-A of the benzoate salt of Compound (I), wherein the molar ratio between Compound (I) and benzoic acid is 1:1. [Figure 6B] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form 2-A of the benzoate salt of Compound (I), where the molar ratio between Compound (I) and benzoic acid is 1:1. [Figure 6C] 1 shows a differential scanning calorimetry (DSC) thermogram of Form 2-A of the benzoate salt of Compound (I), where the molar ratio between Compound (I) and benzoic acid is 1:1. [Figure 7] 1 shows the X-ray powder diffraction (XRPD) pattern of Form 2-B of the benzoate salt of Compound (I), wherein the molar ratio between Compound (I) and benzoic acid is 1:1. [Figure 8A]1 shows the X-ray powder diffraction (XRPD) pattern of Form 9-A of the sulfate salt of Compound (I), where the molar ratio between Compound (I) and sulfuric acid is 1:1. [Figure 8B] 1 shows a differential scanning calorimetry (DSC) thermogram of Form 9-A of the sulfate salt of Compound (I), where the molar ratio between Compound (I) and sulfuric acid is 1:1. [Figure 9A] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of the free base form FB-A-0 of Compound (I). [Figure 9B] 1 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of the crystalline free base of Compound (I). [Figure 9C] 1 shows a differential scanning calorimetry (DSC) thermogram of the crystalline free base of Compound (I). [Figure 10] 1 shows the X-ray powder diffraction (XRPD) pattern of the free base form of Compound (I), FB-A-1. [Figure 11] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of the free base form of Compound (I), FB-A-2. [Figure 12] 1 shows the X-ray powder diffraction (XRPD) pattern of the amorphous phosphate salt of Compound (I). [Figure 13] 1 shows a DSC thermogram of the lyophilized amorphous phosphate salt of Compound (I). [Figure 14] Figure 1 shows X-ray powder diffraction (XRPD) patterns of amorphous Compound (I) free base prepared from lyophilization of the crystalline solid in various solvent systems: (1) amorphous from ACN:water (7:3 by volume), (2) amorphous from t-BuOH (LC), and (3) amorphous from t-BuOH:water (9:1 by volume). [Figure 15] 1 shows the X-ray powder diffraction (XRPD) pattern of the free base of Compound (I) prepared from Example 10. Instrument: Bruker D8 Advance X-ray diffractometer, X-ray source: Cu / K, (λ=1.54056 Å), operating power: 40 kV, 40 mA, start angle: 4°; stop angle: 40°, increment: 0.05 degree / step, scan rate: 0.5 sec / step. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present disclosure relates to i) pharmaceutically acceptable salts of Compound (I); ii) novel solid forms of the free base of Compound (I) and novel solid forms of pharmaceutically acceptable salts of Compound (I), including unsolvated, solvated, amorphous, and crystalline forms (hereinafter collectively referred to as "the salts and solid forms of the present disclosure"); and iii) methods of using and preparing the salts and solid forms of the present disclosure.

[0022] Phosphate of Compound (I) In one aspect, the present disclosure provides a phosphate salt of Compound (I), wherein the molar ratio between Compound (I) and phosphoric acid is 1:1.

[0023] In some embodiments, the phosphonate is crystalline. In some embodiments, the phosphate is in a single crystalline form.

[0024] In some embodiments, the phosphate salt is unsolvated. In other embodiments, the phosphate salt is solvated.

[0025] In some embodiments, the present disclosure provides crystalline Form A of the phosphate salt of Compound (I). The XRPD pattern and peaks are shown in Figure 1A. The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in Figure 1B. [Table 1] Only peaks with a relative intensity of 3 or greater are reported. [Table 2] [Table 3] [Table 4]

[0026] In some embodiments, the present disclosure provides crystalline Form G of the phosphate salt of Compound (I). The XRPD pattern and peaks are shown in Figures 2A and 2B. The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in Figures 2C and 2D. [Table 5] Only peaks with a relative intensity of 0.5 or greater are reported. [Table 6] Only peaks with a relative intensity of 0.5 or greater are reported. [Table 7] [Table 8]

[0027] In some embodiments, the present disclosure provides crystalline Form O of the phosphate salt of Compound (I). The XRPD pattern and peaks are shown in FIG. [Table 9] Only peaks with a relative intensity of 5 or greater are reported. [Table 10] [Table 11] [Table 12]

[0028] Besylate of Compound (I) In one aspect, the present disclosure provides a besylate salt of Compound (I), wherein the molar ratio between Compound (I) and benzenesulfonic acid is 1:2.

[0029] In some embodiments, the besylate salt is crystalline. In some embodiments, the besylate salt is in a single crystalline form.

[0030] In some embodiments, the besylate salt is unsolvated. In other embodiments, the besylate salt is solvated.

[0031] In some embodiments, the present disclosure provides crystalline Form 1-A of the besylate salt of Compound (I). The XRPD pattern and peaks are shown in Figure 4A. The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in Figures 4B and 4C. [Table 13] Only peaks with a relative intensity of 5 or greater are reported. [Table 14] [Table 15] [Table 16]

[0032] In some embodiments, the present disclosure provides crystalline Form 1-B of the besylate salt of Compound (I). The XRPD pattern and peaks are shown in Figure 5. [Table 17] Only peaks with a relative intensity of 5 or greater are reported. [Table 18] [Table 19] [Table 20]

[0033] Benzoate of Compound (I) In one aspect, the present disclosure provides a benzoate salt of Compound (I), wherein the molar ratio between Compound (I) and benzoic acid is 1:1.

[0034] In some embodiments, the Benzoate Salt is crystalline. In some embodiments, the Benzoate Salt is in a single crystalline form.

[0035] In some embodiments, the benzoate salt is unsolvated. In other embodiments, the benzoate salt is solvated.

[0036] In some embodiments, the present disclosure provides crystalline Form 2-A of the benzoate salt of Compound (I). The XRPD pattern and peaks are shown in Figure 6A. The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in Figures 6B and 6C. [Table 21] Only peaks with a relative intensity of 5 or greater are reported. [Table 22] [Table 23] [Table 24]

[0037] In some embodiments, the present disclosure provides crystalline Form 2-B of the benzoate salt of Compound (I). The XRPD pattern and peaks are shown in Figure 7. [Table 25] Only peaks with a relative intensity of 5 or greater are reported. [Table 26] [Table 27] [Table 28]

[0038] Sulfate of Compound (I) In one aspect, the present disclosure provides a sulfate salt of Compound (I), wherein the molar ratio between Compound (I) and sulfuric acid is 1:1.

[0039] In some embodiments, the Sulfate Salt is crystalline. In some embodiments, the Sulfate Salt is in a single crystalline form.

[0040] In some embodiments, the sulfate salt is unsolvated. In other embodiments, the sulfate salt is solvated.

[0041] In some embodiments, the present disclosure provides crystalline Form 9-A of the sulfate salt of Compound (I). The XRPD pattern and peaks are shown in Figure 8A. The differential scanning calorimetry (DSC) thermogram is shown in Figure 8B. [Table 29] Only peaks with a relative intensity of 5 or greater are reported. [Table 30] [Table 31] [Table 32]

[0042] Free base of compound (I) In one aspect, the disclosure provides the free base of Compound (I).

[0043] In some embodiments, the free base of Compound (I) is in amorphous form.

[0044] In some embodiments, the free base of Compound (I) is crystalline. In some embodiments, the free base of Compound (I) is in a single crystalline form.

[0045] In some embodiments, the free base of Compound (I) is unsolvated. In other embodiments, the free base of Compound (I) is solvated.

[0046] In some embodiments, the present disclosure provides a crystalline family of form FB-A of the free base of Compound (I), including form FB-A-0 (monohydrate), form FB-A-1 (metastable hydrate), and form FB-A-2 (dehydrate).

[0047] As described herein, a crystalline family is a group of crystalline forms that contain the same crystalline form but may be described as "interconverting" due to the different amounts of water present in the crystal lattice, which results in slight peak shifts in XRPD.

[0048] The crystalline family of Form FB-A-0 has been found to be a channel hydrate, which can accommodate different amounts of water in the crystal lattice depending on the ambient humidity. The XRPD pattern and peaks are shown in Figure 9A. [Table 33] Only peaks with a relative intensity of 5 or greater are reported. [Table 34] [Table 35] [Table 36]

[0049] In some embodiments, the present disclosure provides crystalline form FB-A-1 of the free base of Compound (I). The XRPD pattern and peaks are shown in FIG. [Table 37] Only peaks with a relative intensity of 3 or greater are reported. [Table 38] [Table 39] [Table 40]

[0050] In some embodiments, the present disclosure provides crystalline form FB-A-2 of the free base of Compound (I). The XRPD pattern and peaks are shown in Figure 11. [Table 41] Only peaks with a relative intensity of 5 or greater are reported. [Table 42] [Table 43] [Table 44]

[0051] In some embodiments, the present disclosure provides a compound of the formula: [ka] wherein the crystalline form is: (a) An X-ray powder diffraction pattern (XRPD) substantially the same as that shown in Figure 9A, 10, or 11; (b) an X-ray powder diffraction pattern (XRPD) comprising at least three peaks selected from 10.6°, 12.2°, 14.2°, 14.8°, 17.1°, 18.3°, 23.1°, and 24.1°; (c) Thermogravimetric analysis (TGA) substantially similar to Figure 9B; (d) DSC thermogram substantially similar to Figure 9C; (e) a DSC thermogram with endotherms with onset temperatures at 61.6±2°C and 171.4±2°C; or (f) any combination thereof; Form A family crystalline forms selected from Form FB-A-0, Form FB-A-1, and Form FB-A-2, characterized by at least one of:

[0052] Pharmaceutical Compositions Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a salt or solid form of the present disclosure and a pharmaceutically acceptable excipient. Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a phosphate salt of Compound (I), wherein the molar ratio between Compound (I) and phosphoric acid is 1:1. In some embodiments, the phosphonate salt is crystalline. In some embodiments, the phosphate salt is in a single crystalline form. In some embodiments, the phosphate salt is unsolvated. In other embodiments, the phosphate salt is solvated. In some embodiments, the phosphate salt of Compound (I) is crystalline form A. In some embodiments, the phosphate salt of Compound (I) is crystalline form G. In some embodiments, the phosphate salt of Compound (I) is crystalline form O.

[0053] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a besylate salt of Compound (I), wherein the molar ratio between Compound (I) and benzenesulfonic acid is 1:2. In some embodiments, the besylate salt is crystalline. In some embodiments, the besylate salt is in a single crystalline form. In some embodiments, the besylate salt is unsolvated. In other embodiments, the besylate salt is solvated. In some embodiments, the besylate salt of Compound (I) is in crystalline Form 1-A. In some embodiments, the besylate salt of Compound (I) is in crystalline Form 1-B.

[0054] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a benzoate salt of Compound (I), wherein the molar ratio between Compound (I) and benzoic acid is 1:1. In some embodiments, the benzoate salt is crystalline. In some embodiments, the benzoate salt is in a single crystalline form. In some embodiments, the benzoate salt is unsolvated. In other embodiments, the benzoate salt is solvated. In some embodiments, the benzoate salt of Compound (I) is in crystalline form 2-A. In some embodiments, the benzoate salt of Compound (I) is in crystalline form 2-B.

[0055] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a sulfate salt of Compound (I), wherein the molar ratio between Compound (I) and sulfuric acid is 1:1. In some embodiments, the sulfate salt is crystalline. In some embodiments, the sulfate salt is in a single crystalline form. In some embodiments, the sulfate salt is unsolvated. In other embodiments, the sulfate salt is solvated. In some embodiments, the sulfate salt of Compound (I) is in crystalline form 9-A.

[0056] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and Compound (I) free base. In some embodiments, the free base is in an amorphous form. In some embodiments, the free base is crystalline. In some embodiments, the free base is in a single crystalline form. In some embodiments, the free base is unsolvated. In other embodiments, the free base is solvated. In some embodiments, Compound (I) free base is in crystalline form FB-A-0. In some embodiments, Compound (I) free base is in crystalline form FB-A-1. In some embodiments, Compound (I) free base is in crystalline form FB-A-2.

[0057] The salts or solid forms of the present disclosure can be formulated for administration in any convenient manner for use in human or veterinary medicine. In some embodiments, the compounds or salts included in the pharmaceutical compositions may be active themselves or may be, for example, prodrugs that can be converted to active compounds in physiological environments.

[0058] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0059] Examples of pharmaceutically acceptable carriers / excipients include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; and (10) propylene glycol. (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; (21) cyclodextrins, such as Captisol®; and (22) other non-toxic, compatible substances used in pharmaceutical formulations.

[0060] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0061] Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, etc.) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) agar, charcoal, or the like; (5) disintegrating agents such as calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (6) solution retarders such as paraffin; (7) absorption accelerators such as quaternary ammonium compounds; (8) wetting agents such as cetyl alcohol and glycerol monostearate; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

[0062] Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and their mixtures.

[0063] In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, agar, tragacanth, and mixtures thereof.

[0064] The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, zinc oxide, or mixtures thereof.

[0065] Powders and sprays may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0066] The salts or solid forms of the present disclosure can be obtained by themselves or in combination with a pharmaceutically acceptable carrier, for example, as a pharmaceutical composition containing 0.1 to 99.5% (such as 0.5 to 90%) of the active ingredient.

[0067] Formulations may be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intravesically, intradermally, intraperitoneally, subcutaneously, subepidermally, or by inhalation.

[0068] Treatment method Some embodiments of the present disclosure relate to methods of treating a patient in need of a KIT or PDGFRα inhibitor by administering a therapeutically effective amount of a salt or solid form of the present disclosure.

[0069] The salts and solid forms of the present disclosure are selective KIT inhibitors. In some embodiments, the salts and solid forms of the present disclosure are selective D816V KIT inhibitors. In some embodiments, the salts and solid forms of the present disclosure are selective PDGFRα inhibitors. In some embodiments, the salts and solid forms of the present disclosure are selective PDGFRα exon 18 inhibitors. In some embodiments, the salts and solid forms of the present disclosure are selective PDGFRα D842V inhibitors. As used herein, "selective KIT inhibitor" or "selective PDGFRα inhibitor" refers to a salt or solid form of the present disclosure that selectively inhibits KIT protein kinase or PDGFRα protein kinase over another protein kinase, and exhibits at least 2-fold selectivity for KIT protein kinase or PDGFRα protein kinase over another kinase. For example, a selective KIT inhibitor or a selective PDGFRA inhibitor exhibits at least 9-fold selectivity, 10-fold selectivity, at least 15-fold selectivity, at least 20-fold selectivity, at least 30-fold selectivity, at least 40-fold selectivity, at least 50-fold selectivity, at least 60-fold selectivity, at least 70-fold selectivity, at least 80-fold selectivity, at least 90-fold selectivity, at least 100-fold, at least 125-fold, at least 150-fold, at least 175-fold, or at least 200-fold selectivity for KIT protein kinase or PDGFRA kinase over another kinase. In some embodiments, a selective KIT inhibitor or a selective PDGFRA inhibitor exhibits at least 150-fold selectivity over another kinase, such as VEGFR2 (vascular endothelial growth factor receptor 2), SRC (non-receptor protein tyrosine kinase), and FLT3 (Fms-like tyrosine kinase 3). In some embodiments, the selective KIT or selective PDGFRα inhibitor exhibits selectivity over PDGRFβ, CSF1R (colony stimulating factor receptor 1), and FLT3.

[0070] In some embodiments, the selective KIT or PDGFRα inhibitor exhibits selectivity over LCK (lymphocyte-specific protein kinase), ABL (nuclear protein tyrosine kinase), never-in-mitosis gene A (NIMA)-associated kinase 5 (NEK5), and ROCK1 (rho-associated coil-coil-continuing protein kinase-1). In some embodiments, selectivity for KIT protein kinase or PDGFRα protein kinase over another kinase is measured in a cellular assay (e.g., a cellular assay). In some embodiments, selectivity for KIT protein kinase or PDGFRα protein kinase over another kinase is measured in a biochemical assay (e.g., a biochemical assay).

[0071] The salts and solid forms of the present disclosure are selective for ion channels, in some embodiments, selective KIT or selective PDGFRα inhibitors have limited potency in inhibiting the human voltage-gated sodium channel (hNav 1.2).

[0072] The salts and solid forms of the present disclosure are selective for mutant KIT over wild-type KIT, hi some embodiments, the salts and solid forms of the present disclosure are selective for exon 17 mutant KIT over wild-type KIT.

[0073] The salts and solid forms of the present disclosure may be useful for treating diseases or conditions associated with mutant KIT or mutant PDGFRA activity in humans or non-humans. In some embodiments, the salts and solid forms of the present disclosure are for use as pharmaceuticals. In some embodiments, the salts and solid forms of the present disclosure are for use in therapy. In some embodiments, the salts and solid forms of the present disclosure are for use in the manufacture of a medicament. In some embodiments, the present disclosure provides methods for treating KIT-driven malignancies, including mastocytosis (SM), GIST (gastrointestinal stromal tumor), AML (acute myeloid leukemia), melanoma, seminoma, intracranial germ cell tumor, and / or mediastinal B-cell lymphoma. Furthermore, mutations in KIT have been associated with Ewing's sarcoma, DLBCL (diffuse large B-cell lymphoma), dysgerminoma, MDS (myelodysplastic syndrome), NKTCL (nasal NK / T-cell lymphoma), CMML (chronic myelomonocytic leukemia), and brain cancer. In some embodiments, the present disclosure provides methods for treating Ewing's sarcoma, DLBCL, dysgerminoma, MDS, NKTCL, CMML, and / or brain cancer. KIT mutations have also been found in thyroid cancer, colorectal cancer, endometrial cancer, bladder cancer, NSCLC, and breast cancer (AACR Project GENIE). In some embodiments, the salts and solid forms of the present disclosure may be useful for treating mast cell activation syndrome (MCAS). The salts and solid forms of the present disclosure may be useful for treating systemic mastocytosis. The salts and solid forms of the present disclosure may be useful for treating advanced systemic mastocytosis. The salts and solid forms of the present disclosure may be useful for treating indolent SM and smoldering SM. The salts and solid forms of the present disclosure may be useful for treating GIST.

[0074] The salts and solid forms of the present disclosure may be useful for treating a disease or condition associated with a KIT mutation in exon 9, exon 11, exon 14, exon 17, and / or exon 18 of the KIT gene sequence. The salts and solid forms of the present disclosure may be useful for treating a disease or condition associated with a PDGFRA mutation in exon 12, exon 14, and / or exon 18 of the PDGFRA gene sequence. In some embodiments, provided herein are methods for treating a disease or condition associated with at least one KIT mutation in exon 9, exon 11, exon 14, exon 17, and / or exon 18 of the KIT gene sequence. In some embodiments, provided are methods for treating a disease or condition associated with at least one PDGFRA mutation in exon 12, exon 14, and / or exon 18 of the PDGFRA gene sequence.

[0075] The salts and solid forms of the present disclosure may be active against one or more KIT protein kinases having mutations in exon 17 of the KIT gene sequence (e.g., KIT protein mutations D816V, D816Y, D816F, D816K, D816H, D816A, D816G, D816E, D816I, D816F, D820A, D820E, D820G, D820Y, N822K, N822H, V560G, Y823D, and A829P), and can be much less active against wild-type KIT protein kinase. In some embodiments, provided herein are methods for treating a disease or condition associated with at least one KIT mutation, such as a KIT mutation selected from D816V, D816Y, D816F, D816K, D816H, D816A, D816G, D816E, D816I, D816F, D820A, D820E, D820G, D820Y, N822K, N822H, V560G, Y823D, and A829P. In some embodiments, provided herein are methods for treating a disease or condition associated with at least one KIT mutation, such as a KIT mutation selected from C809, C809G, D816H, D820A, D820G, N822H, N822K, and Y823D.

[0076] The salts and solid forms of the present disclosure may be active against one or more KIT protein kinases having a mutation in exon 11 of the KIT gene sequence (eg, the KIT protein mutation del557-559insF, V559G / D). In some embodiments, for example, L576P, V559D, V560D, V560G, W557G, Del 554-558EVQWK, del557-559insF, Del EVQWK554-558, Del EVQWKVVEEINGNNYVYI554-571, Del KPMYEVQWK550-558, Del KPMYEVQW550-557FL, Del KV558-559, Del KV558-559N, Del MYEVQW552-557, Del PMYE551-554, Del VV559-560, Del WKVVE557-561, Del WK557-558, Del WKVV557-560C, Del Provided herein are methods for treating a disease or condition associated with at least one KIT mutation, such as a KIT mutation selected from WKVV557-560F, DelYEVQWK553-558, and the insertion K558NP.

[0077] The salts and solid forms of the present disclosure may be active against one or more KIT protein kinases having mutations in exons 11 / 13 of the KIT gene sequence (e.g., KIT protein mutations V559D / V654A, V560G / D816V, and V560G / 822K). In some embodiments, provided herein are methods for treating diseases or conditions associated with one or more KIT mutations in exons 11 / 13.

[0078] The salts and solid forms of the present disclosure may be active against one or more KIT protein kinases having a mutation in exon 9 of the KIT gene sequence. In some embodiments, provided herein are methods for treating a disease or condition associated with at least one KIT mutation in exon 9.

[0079] In some embodiments, the salts and solid forms of the present disclosure have no activity against KIT protein kinases with mutations V654A, N655T, T670I, and / or N680.

[0080] The salts and solid forms of the present disclosure may be active against one or more PDGFRα protein kinases harboring mutations. In some embodiments, provided herein are methods for treating a disease or condition associated with at least one PDGFRA mutation in exon 12 of the PDGFRA gene sequence, such as, for example, the PDGFRα protein mutation V561D, Del RV560-561, Del RVIES560-564, Ins ER561-562, SPDGHE566-571R, SPDGHE566-571K, or Ins YDSRW582-586. In some embodiments, provided herein are methods for treating a disease or condition associated with at least one PDGFRA mutation in exon 14 of the PDGFRA gene sequence, such as, for example, the PDGFRα protein mutation N659K. In some embodiments, for example, PDGFRα protein mutations D842V, D842Y, D842I, DI842-843IM, D846Y, Y849C, Del D842, Del I843, Del RD841-842, Del DIM842-845, Del DIMH842-845, Del IMHD843-846, Del Provided herein are methods for treating a disease or condition associated with at least one PDGFRA mutation in exon 18 of the PDGFRA gene sequence, such as DIMHDS844-847, RD841-842KI, DIMH842-845A, DIMH842-845V, DIMHD842-846E, DIMHD842-846S, DIMHD842-846N, DIMHD842-846G, IMHDS843-847T, IMHDS8843-847M, or HDSN845-848P.

[0081] The salts and solid forms of the present disclosure may be active against one or more PDGFRα protein kinases having a mutation in exon 18 in the PDGFRA gene sequence (e.g., the protein mutations PDGFRα D842V, PDGFRα D842I, or PDGFRα D842Y). In some embodiments, provided herein are methods for treating a disease or condition associated with at least one PDGFRA mutation in exon 18, such as, for example, the protein mutation PDGFRα D842V.

[0082] The salts and solid forms of the present disclosure may be useful for treating eosinophilic disorders. In some embodiments, the eosinophilic disorder is mediated by mutant KIT or PDGFRα. In some embodiments, the eosinophilic disorder is mediated by wild-type KIT or PDGFRα. In some embodiments, provided herein are methods for treating eosinophilic disorders, comprising administering to a subject a therapeutically effective amount of a salt and solid form of the present disclosure, or a pharmaceutically acceptable salt and / or solvate of any of the foregoing. In one embodiment, the eosinophilic disorder is selected from hypereosinophilic syndrome, eosinophilia, eosinophilic enterogastritis, eosinophilic leukemia, eosinophilic granuloma, and Kimura's disease.

[0083] In some embodiments, the eosinophilic disorder is selected from hypereosinophilic syndrome, eosinophilia, eosinophilic enterogastritis, eosinophilic leukemia, eosinophilic granuloma, and Kimura's disease. Other eosinophilic disorders include eosinophilic esophagitis, eosinophilic gastroenteritis, eosinophilic fasciitis, and Churg-Strauss syndrome.

[0084] In one embodiment, the eosinophilic disorder is hypereosinophilic syndrome. In a specific embodiment, the hypereosinophilic syndrome is idiopathic hypereosinophilic syndrome. In one embodiment, the eosinophilic disorder is eosinophilic leukemia. In a specific embodiment, the eosinophilic leukemia is chronic eosinophilic leukemia. In another embodiment, the eosinophilic disorder is refractory to treatment with imatinib, sunitinib, and / or regorafenib. In a specific embodiment, the eosinophilic disorder is refractory to treatment with imatinib.

[0085] The salts and solid forms of the present disclosure can be useful for reducing the number of eosinophils in a subject in need thereof. In some embodiments, provided herein are methods for reducing the number of eosinophils in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of the salts and solid forms of the present disclosure, or pharmaceutically acceptable salts and / or solvates of any of the foregoing.

[0086] In one embodiment, the disclosed methods reduce the number of eosinophils in the blood, bone marrow, gastrointestinal tract (e.g., esophagus, stomach, small intestine, and colon), or lungs. In another embodiment, the methods disclosed herein reduce the number of blood eosinophils. In a further embodiment, the methods disclosed herein reduce the number of lung eosinophils. In a still further embodiment, the methods disclosed herein reduce the number of eosinophil progenitor cells.

[0087] In another embodiment, the disclosed methods reduce the number of eosinophils (after administration) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%. In certain embodiments, the methods disclosed herein reduce the number of eosinophils below the limit of detection.

[0088] In another embodiment, the disclosed methods reduce the number of eosinophil precursors (after administration) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%. In certain embodiments, the methods disclosed herein reduce the number of eosinophil precursors below the limit of detection.

[0089] The salts and solid forms of the present disclosure may be useful for treating mast cell disorders. The salts and solid forms of the present disclosure may be useful for treating mastocytosis. Mastocytosis is subdivided into two groups of disorders: (1) cutaneous mastocytosis (CM), which describes forms limited to the skin, and (2) systemic mastocytosis (SM), which describes forms in which mast cells infiltrate organs outside the dermis, with or without skin lesions. SM is further subdivided into five forms: indolent (ISM), smoldering (SSM), aggressive (ASM), SM with associated hemotologic non-mast cell lineage disease (SM-AHNMD), and mast cell leukemia (MCL).

[0090] The diagnosis of SM is based in part on histologic and cytologic examination of bone marrow, which demonstrates infiltration by morphologically atypical mast cells that frequently aberrantly express non-mast cell markers (CD25 and / or CD2). The diagnosis of SM is confirmed when mast cell infiltration in the bone marrow occurs in association with one of the following: (1) abnormal mast cell morphology (spindle-shaped cells), (2) elevated serum tryptase levels greater than 20 ng / mL, or (3) the presence of an activating KIT protein mutation, such as an exon 17 mutation, e.g., a D816 mutation, e.g., D816V.

[0091] Activating mutations at position D816 are found in the majority of mastocytosis cases (90-98%), with the most common mutations being D816V, D816H, and D816Y. The D816V mutation is found in the activation loop of the protein kinase domain and leads to constitutive activation of the KIT kinase.

[0092] There are no approved medications for non-progressive systemic mastocytosis (ISM) or systemic mastocytosis (SSM). Current approaches to managing these chronic diseases include non-specific symptom-directed treatments, which have varying degrees of effectiveness and are ineffective against MC burden. Cytoreductive therapies, such as cladribine and interferon alpha, are occasionally used for refractory symptoms. Based on the current treatment landscape, there is an unmet medical need in patients with ISM and SSM with moderate to severe symptoms that cannot be adequately managed with available symptom-directed treatments.

[0093] The salts and solid forms of the present disclosure may be useful for treating ISM or SSM. In some embodiments, patients with ISM or SSM have at least one, at least two, or at least three symptoms that are not adequately controlled by symptomatic treatment. Symptoms may be assessed using a patient-reported outcome (PRO) tool, such as the Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) (ISPOR Europe 2019, Copenhagen Denmark, 2-6 Nov 2019). The salts and solid forms of the present disclosure may be useful for improving symptoms associated with ISM or SSM, for example, reducing or eliminating itching, flushing, headache, and / or GI events such as vomiting, diarrhea, and abdominal pain. Symptom improvement may be assessed using the ISM-SAF.

[0094] The salts and solid forms of the present disclosure may be useful for treating other mast cell disorders, such as mast cell activation syndrome (MCAS) and hereditary alpha tryptasia (HAT) (Picard Clin. Ther. 2013, May 35(5)548; Akin J. Allergy Clin. Immuno. 140(2)349 62). The salts and solid forms of the present disclosure may be useful for treating mast cell disorders associated with KIT and PDGFRα mutations. The salts and solid forms of the present disclosure may be useful for treating mast cell diseases associated with wild-type KIT and PDGFRα.

[0095] The salts and solid forms of the present disclosure may be useful for treating mast cell activation syndrome (MCAS), an immunological condition in which mast cells inappropriately and excessively release chemical mediators, resulting in a variety of chronic symptoms, sometimes including anaphylactic or near-anaphylactic attacks. Unlike mastocytosis, in which patients have an abnormally increased number of mast cells, patients with MCAS have a normal number of mast cells that do not function properly and are defined as "hyperresponsive." Types of MCAS include primary MCAS (monoclonal mast cell activation syndrome (MMAS)), secondary MCAS (MCAS arising from another disease), and idiopathic MCAS (MCAS excluding primary or secondary MCAS).

[0096] Disclosed herein are improved methods for treating indolent systemic mastocytosis (ISM) and monoclonal mast cell activation syndrome in patients with Compound (I) or a pharmaceutically acceptable salt thereof (e.g., the salts and solid forms of the present disclosure). The present disclosure provides dosing regimens of Compound (I) for the treatment of ISM and mMCAS. More specifically, the present disclosure provides methods for treating ISM and mMCAS in patients by administering a once-daily dose of Compound (I) in an amount of 15 mg to 200 mg. An object of the present disclosure is to provide a new method for treating ISM and mMCAS with a safe and effective once-daily dose.

[0097] Non-limiting embodiments of the present disclosure include the following:

[0098] Embodiment 1. A method of treating indolent systemic mastocytosis (ISM) or monoclonal mast cell activation syndrome (mMCAS), comprising administering to a patient in need thereof an amount of 15 mg to 200 mg of Compound (I). [ka] Alternatively, the method comprises orally administering 15 mg to 200 mg of compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to the compound (I) once a day.

[0099] Embodiment 2. The method of embodiment 1, wherein the patient has ISM.

[0100] Embodiment 3. The method of embodiment 1 or 2, wherein the patient has moderate to severe ISM.

[0101] Embodiment 4. The method of embodiment 3, wherein the patient has a baseline Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) of ≥ 28. In an alternative embodiment, the patient has a baseline ISM-SAF TSS < 28.

[0102] Embodiment 5. The method of any of embodiments 1-4, wherein the patient has ≧1 symptom in the skin or GI area of ​​the Painless Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) at baseline.

[0103] Embodiment 6. The method of embodiment 1, wherein the patient has mMCAS.

[0104] Embodiment 7. The method of any one of embodiments 1 to 6, wherein the amount is 25 to 100 mg.

[0105] Embodiment 8. The method of embodiment 7, wherein the amount is 100 mg.

[0106] Embodiment 9. The method of embodiment 7, wherein the amount is 50 mg.

[0107] Embodiment 10. The method of embodiment 7, wherein the amount is 25 mg.

[0108] Embodiment 11. The method of any one of embodiments 1 to 10, wherein Compound (I) is administered as the free base.

[0109] Embodiment 12. The method of any one of embodiments 1 to 10, wherein Compound (I) is administered as a pharmaceutically acceptable salt.

[0110] Embodiment 13. The method of embodiment 12, wherein the pharmaceutically acceptable salt of Compound (I) is the salt. In some aspects, the salt is a phosphate salt. In some aspects, the salt is a besylate salt. In some aspects, the salt is a benzoate salt. In some aspects, the salt is a sulfate salt.

[0111] Embodiment 14. The method of any one of embodiments 1 to 13, wherein treatment results in a reduction in mast cell mass.

[0112] Embodiment 15. The method of any one of embodiments 1-14, wherein the treatment results in one or more symptoms of systemic mastocytosis.

[0113] Embodiment 16. The method of any one of embodiments 1 to 15, wherein treatment results in a reduction in anaphylactic episodes.

[0114] Embodiment 17. The method of any one of embodiments 1-16, wherein the treatment results in an improvement in quality of life (QoL) as measured by one or more questionnaires.

[0115] Embodiment 18. The method of any one of embodiments 1-17, wherein treatment results in a decrease in the patient's TSS score compared to the patient's TSS baseline score as assessed by ISM-SAF.

[0116] In some embodiments, the patient is administered Compound (I) as the free base (including the various solid forms of the free base disclosed herein). In some embodiments, the patient is administered Compound (I) as a pharmaceutically acceptable salt (including the various solid forms of the pharmaceutically acceptable salts disclosed herein). In some embodiments, the pharmaceutically acceptable salt is a phosphate salt.

[0117] In some embodiments, treating a patient with an amount of Compound (I) or a pharmaceutically acceptable salt thereof disclosed herein reduces mast cell mass. In some embodiments, objective measures of mast cell mass include serum tryptase levels, bone marrow mast cell count, skin mast cell infiltration, and blood KIT D816V mutant allele load. In some embodiments, objective measures of mast cell mass include serum tryptase, bone marrow mast cell count, and blood KIT D816V mutant allele load. In some embodiments, treating a patient with 50 mg of Compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof reduces the patient's serum tryptase level. In some embodiments, treating a patient with 100 mg of Compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof reduces the patient's serum tryptase level.

[0118] In some embodiments, treatment of a patient with Compound (I) or a pharmaceutically acceptable salt thereof in an amount disclosed herein includes a reduction in one or more symptoms of systemic mastocytosis. Symptoms of systemic mastocytosis include, but are not limited to, itching, flushing, GI cramps, diarrhea, anaphylaxis (especially to bee venom), bone pain, osteoporosis, and urticaria pigmentosa. In some embodiments, symptom improvement is assessed using the ISM-SAF (Self-Assessment Form) patient-reported outcome (PRO) scale as defined herein. In some embodiments, the patient completes the ISM-SAF once daily before receiving treatment, and the patient also completes the ISM-SAF once daily while receiving treatment. For example, the patient completes the ISM-SAF for a period of time, e.g., four weeks, beginning at the time of informed consent, during which best supportive care (BSC) medication is optimized and stabilized. Once data from a set period, e.g., 4 weeks, has been collected, the ISM-SAF is completed once daily for an additional set period, e.g., 2 weeks (14 days), and patient eligibility is determined based on the symptom threshold according to the ISM-SAF. Patients who meet the ISM-SAF threshold for eligibility then complete the ISM-SAF once daily while completing screening procedures to assess study eligibility.

[0119] Once all screening procedures are completed, baseline symptoms are collected for a period of time, for example, 14 days, immediately prior to study enrollment. These data are used as the baseline TSS. The ISM-SAF is completed by patients once daily until study completion. In some embodiments, the primary endpoint of the study is the mean change in ISM-SAF TSS from baseline. In some embodiments, treatment with Compound (I) or a pharmaceutically acceptable salt thereof reduces the number of anaphylactic episodes. In some embodiments, an "anaphylactic episode" is an anaphylactic episode treated with epinephrine.

[0120] In some embodiments, treating a patient with Compound (I) or a pharmaceutically acceptable salt thereof in an amount disclosed herein improves quality of life (QoL) as measured by one or more questionnaires. Non-limiting examples of QoL questionnaires include MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-EL. MC-QoL is a disease-specific QoL tool specifically developed for use in patients with ISM and CM (Siebenhaar, F. et al., Allergy 71(6):869-77(2016)). MC-QoL includes 27 items assessing four domains: symptoms, emotions, social life / function, and skin. Items are rated on a 5-point scale with a 2-week recall period. PGIS is a single-item scale that assesses a patient's perception of disease symptoms at a given time point. PGIS is widely used to assess a patient's overall sense of whether treatment is beneficial. The SF-12 was developed for a medical outcomes study, a multiyear study of patients with chronic conditions. This scale was designed to reduce respondent burden while achieving a minimum standard of precision for group comparisons involving multiple health dimensions. The questionnaire measures health and well-being using eight health domains from the patient's perspective. The recall period is 4 weeks. The PGIC is a single-item scale that assesses patients' perceptions of change in disease symptoms at a given time point. The EQ-5D-5L is a standardized measure for measuring general health status. It consists of two components: a description and an evaluation of health status. Health status is measured in terms of five dimensions (5Ds): mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Respondents self-rate the level of severity of each dimension using a 5-point scale. The recall period is "today" (Whynes, DK, Health Qual Life Outcomes 6:94 (2008)).

[0121] In some embodiments, treatment of a patient with Compound (I) or a pharmaceutically acceptable salt thereof in an amount disclosed herein improves bone mineral density. Bone mineral density is measured by dual-energy X-ray absorptiometry, assessing both the lumbar spine and hip joints. In some embodiments, treatment does not affect bone mineral density.

[0122] As used herein, "SD" means stable disease.

[0123] As used herein, "CR" means complete response.

[0124] As used herein, "PFS" means progression-free survival.

[0125] As used herein, the "Indolent Systemic Mastocytosis - Symptom Assessment Form" (© Blueprint Medicines Corporation) or "ISM-SAF" (ISPOR Europe 2019, Copenhagen Denmark, 2-6 Nov 2019) is used for daily patient-reported outcomes (PRO) assessment, e.g., in an eDiary. The ISM-SAF is a 12-item PRO specifically developed to assess symptoms in patients with ISM and SSM. Although developed primarily to evaluate hypotheses of treatment efficacy, the ISM-SAF can also be used to screen participants for inclusion in (or exclusion from) clinical trials based on minimal levels of sign and symptom severity. The 11 items shown in the table below are scored on a 10-point scale (0 to 10, none to maximal severity), and one item (diarrhea) also assesses frequency. [Table 45]

[0126] The ISM-SAF generates scores for each of the following domains: Skin / Skin Symptom Score (SSS), GI / Gastrointestinal Symptom Score (GSS), and Nonspecific Symptoms, as well as a Total Symptom Score (TSS). The TSS is the sum of all symptoms. In one embodiment, the TSS is items 1-10 and 12. In one embodiment, the GSS is items 2-3 and 12. In one embodiment, the SSS is items 4-6. In one embodiment, patients complete the ISM-SAF daily for four weeks, beginning at the time of informed consent, during which time their medication with the BSC is optimized and stabilized. Once four weeks of data have been collected, the ISM-SAF is completed daily for an additional two weeks (14 days) to determine patient eligibility based on the ISM-SAF symptom threshold. Patients who meet the ISM-SAF threshold for eligibility complete the ISM-SAF daily while completing screening procedures to assess study eligibility. Once all screening procedures are completed, baseline symptoms will be collected for 14 days immediately prior to study enrollment. These data will be used as the baseline TSS.

[0127] In one embodiment, patients with ISM have moderate to severe symptoms characterized by a minimal TSS. In one embodiment, patients with ISM have moderate to severe symptoms characterized by a minimal TSS of ≧28 as assessed using the ISM-SAF. In one embodiment, patients with ISM or SSM with moderate to severe symptoms have a minimal TSS of ≧28 and skin or GI symptoms of ≧1 on the ISM-SAF at baseline. In one embodiment, patients with ISM have a TSS<28. In one embodiment, the baseline is a 14-day period prior to Cycle 1 Day 1 (C1D1). In one embodiment, the patient does not experience an acute flare of symptoms beyond typical baseline symptoms. In one embodiment, the patient has not achieved symptomatic control of one or more baseline symptoms as determined by the investigator with at least two of the following symptomatic therapies: H1 blockers, H2 blockers, proton pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab, administered at optimal (approved) doses for a minimum of 4 weeks (28 days) prior to initiation of the ISM-SAF to determine eligibility. In one embodiment, the patient has a baseline serum tryptase of <20 ng / mL. In one embodiment, the patient has a baseline serum tryptase of ≥20 ng / mL.

[0128] In one embodiment, treatment of a patient with Compound (I) or a pharmaceutically acceptable salt thereof results in a decrease in the TSS score compared to the patient's baseline TSS score as assessed by ISM-SAF. In one embodiment, the patient's TSS is decreased by 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0129] In one embodiment, a patient with ISM has a KIT D816V mutation, which can be detected by a highly sensitive assay such as a digital droplet polymerase chain reaction (ddPCR) assay with a limit of detection (LOD) of 0.022% mutant allele frequency (MAF).

[0130] As used herein, "BSC" means best supportive care. More specifically, examples of best supportive care medications include: [Table 46]

[0131] In some embodiments, patients treated with Compound (I) or a pharmaceutically acceptable salt disclosed herein are co-administered with a proton pump inhibitor. In some embodiments, patients are treated with Compound (I) or a pharmaceutically acceptable salt disclosed herein and co-administered with a proton pump inhibitor in the fasting state. In some embodiments, patients are treated with Compound (I) or a pharmaceutically acceptable salt disclosed herein and co-administered with a proton pump inhibitor after a moderate-fat meal. In some embodiments, patients are treated with Compound (I) or a pharmaceutically acceptable salt disclosed herein and co-administered with a proton pump inhibitor after a high-fat meal.

[0132] As used herein, an "adverse event" or "AE" is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An AE (also known as an adverse experience) is any untoward and unintended sign (e.g., abnormal clinical laboratory findings), symptom, or disease that is transiently associated with the use of a drug, without any determination of causality. AEs can arise from any use of a drug (e.g., off-label use, concomitant use with another drug), and from any route of administration, formulation, or dose (including overdose).

[0133] As used herein, the terms "about" and "approximately" when used in connection with a dose, amount, or weight percent of a composition or dosage form, or a component thereof, include the specified dose, amount, or weight percent value, or range of doses, amounts, or weight percent that would be recognized by one of skill in the art to provide a pharmacological effect equivalent to that resulting from the specified dose, amount, or weight percent.

[0134] The present disclosure provides a method for treating painless systemic mastocytosis, the method comprising administering to a patient in need thereof an amount of Compound (I) between 15 mg and 200 mg or a pharmaceutically acceptable salt thereof equivalent to 55 mg and 200 mg of Compound (I) once daily. In some embodiments, a patient in need thereof is administered an amount of Compound (I) between 10 mg and 200 mg once daily. In some embodiments, a patient in need thereof is administered 15 mg, 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg of Compound (I) (or a pharmaceutically acceptable salt thereof equivalent to 15 mg, 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg of Compound (I)) once daily. In some embodiments, the amount is 50 mg to 200 mg once daily. In some embodiments, the amount is 100 mg to 200 mg once daily. In some embodiments, the amount is 50 mg to 100 mg once daily.

[0135] The salts and solid forms of the present disclosure may be useful for treating hereditary alphatryptasia (HAT) (elevated tryptase caused by overexpression of TPSAB1).

[0136] Other mast cell disorders include mast cell-mediated asthma, anaphylaxis (including idiopathic, Ig-E mediated, and non-Ig-E mediated), urticaria (including idiopathic and chronic), atopic dermatitis, swelling (angioedema), irritable bowel syndrome, mast cell gastroenteritis, mastocytic colitis, pruritus, chronic pruritus, pruritus secondary to chronic renal failure, and mast cell-associated conditions of the heart, blood vessels, intestine, brain, kidney, liver, pancreas, muscle, bone, and skin. In some embodiments, the mast cell disorder is not associated with mutant KIT or mutant PDGFRα.

[0137] KIT and PDGFRA mutations have been extensively studied in GIST. The salts and solid forms of the present disclosure may be useful for treating GIST associated with KIT mutations. The salts and solid forms of the present disclosure may be useful for treating unresectable or metastatic GIST. Nearly 80% of metastatic GISTs have primary activating mutations in either the extracellular region (exon 9) or the juxtamembrane (JM) domain (exon 11) of the KIT gene sequence. Many mutant KIT tumors respond to treatment with targeted therapies such as imatinib, a selective tyrosine kinase inhibitor that specifically inhibits BCR-ABL, KIT, and PDGFRA proteins. However, most GIST patients ultimately relapse due to secondary mutations in KIT that significantly reduce the binding affinity of imatinib. These resistance mutations always occur within the adenosine 5-triphosphate (ATP)-binding pocket (exons 13 and 14) or activation loop (exons 17 and 18) of the kinase gene. None of the currently approved drugs for GIST are selective targeted agents. Imatinib is currently approved for the treatment of GIST, and multi-targeted kinase inhibitors are used after imatinib. In many cases, these multi-targeted kinase inhibitors, such as sunitinib, regorafenib, and midostaurin, only weakly inhibit imatinib-resistant mutations, and / or multi-targeted kinase inhibitors are limited by more complex safety profiles and narrow therapeutic windows. In some embodiments, the salts and solid forms of the present disclosure may be useful for treating GIST in patients who have been treated with imatinib. The salts and solid forms of the present disclosure may be useful for treating GIST as first-line (1L), second-line (2L), third-line (3L), or fourth-line (4L) therapy.

[0138] The salts and solid forms of the present disclosure may be useful for treating GIST when certain mutations in KIT are absent or present. In some embodiments, the salts and solid forms of the present disclosure can treat GIST when certain mutations in KIT are absent. In certain embodiments, the salts and solid forms of the present disclosure cannot treat GIST when certain mutations in KIT are present. In some embodiments, the salts and solid forms of the present disclosure do not provide clinical utility in patients with mutations in the KIT ATP-binding pocket (KIT protein mutations V654A, N655T, and / or T670I).

[0139] The salts and solid forms of the present disclosure may be useful for treating GIST associated with PDGFRA mutations. In 5-6% of patients with unresectable or metastatic GIST, a mutation at amino acid 842 in the activation loop protein of exon 18 of the PDGFRA gene sequence occurs as the primary mutation.

[0140] The salts and solid forms of the present disclosure may also be useful in the treatment of AML. AML patients also carry KIT mutations, with the majority of these mutations at position D816 of the KIT protein.

[0141] As used herein, Compound (I): [ka] An improved process for the preparation of Form A, a crystalline phosphate salt of Compound (I), is disclosed, comprising forming a phosphate salt of Compound (I) using phosphoric acid in an organic solvent mixture comprising 2-MeTHF / acetone / water. In one embodiment, the ratio of the organic solvent mixture is 1.0 volume 2-MeTHF:1.0 volume acetone:1.3-2.0 volumes water. In one embodiment, the amount of phosphoric acid is 1.1 equivalents to 1.0 equivalent of Compound (I). In one embodiment, the process further comprises crystallizing Form A, a phosphate salt of Compound (I), by adding acetone. In one embodiment, the acetone is added over a period of 4-8 hours.

[0142] The following examples are intended to illustrate, but not to limit the scope of the present disclosure in any way. [Example]

[0143] [Table 47]

[0144] [Table 48]

[0145] [Table 49]

[0146] Analysis conditions X-ray powder diffraction (XRPD) Bruker XRPD of the free base and phosphate salts disclosed herein was performed using a Bruker D8 Advance equipped with a LYNXEYE detector in reflectance mode (i.e., Bragg-Brentano geometry), except for Example 10 (conditions noted therein). Samples were prepared on Si zero-return wafers. Parameters for the XRPD method used are listed below. [Table 50]

[0147] Rigaku X-ray powder diffraction of the besylate, benzoate, and sulfate salts disclosed herein was performed using a Rigaku MiniFlex 600 in reflectance mode (i.e., Bragg-Brentano geometry). Samples were prepared on Si zero-return wafers. The parameters for the XRPD method used are listed below. [Table 51]

[0148] Simultaneous thermogravimetric analysis and differential scanning calorimetry (TGA and DSC) TGA and DSC: Mettler Toledo TGA / DSC 3+ The same samples were analyzed simultaneously using the same ion exchanger. The protective and purge gases were nitrogen at flow rates of 20-30 mL / min and 50-100 mL / min, respectively. The desired amount of sample (5-10 mg) was weighed directly into a tightly sealed aluminum pan with a small hole and analyzed according to the following parameters: [Table 52]

[0149] Differential scanning calorimetry (DSC) DSC is Mettler Toledo DSC 3+ Samples (1-5 mg) were weighed directly into 40 μL hermetically sealed aluminum pans with small holes and analyzed according to the following parameters: [Table 53] [Table 54]

[0150] 1 H-nuclear magnetic resonance spectroscopy ( 1 H-NMR) Proton NMR was performed on a Bruker Avance 300 MHz spectrometer. Solids were dissolved in 0.75 mL of deuterated solvent in 4 mL vials, transferred to NMR tubes (Wilmad 5 mm thin-walled 8 inch, 200 MHz, 506-PP-8) and analyzed according to the following parameters: [Table 55]

[0151] High-performance liquid chromatography (HPLC) HPLC was performed using an Agilent 1220 Infinity LC with an instrument flow rate range of 0.2–5.0 mL / min, an operating pressure range of 0–600 bar, a temperature range of 5°C above ambient to 60°C, and a wavelength range of 190–600 nm.

[0152] HPLC was performed using an Agilent 1220 Infinity 2 LC equipped with a diode array detector (DAD). The instrument flow rate range was 0.2–5.0 mL / min, the operating pressure range was 0–600 bar, the temperature range was 5°C above ambient to 60°C, and the wavelength range was 190–600 nm.

[0153] HPLC was performed using a Hitachi LaChrom HPLC with an instrument flow rate range of 0.2–10.0 mL / min, an operating pressure range of 0–412 bar, a temperature range of 5°C above ambient to 60°C, and a wavelength range of 190–600 nm.

[0154] The HPLC method used in this study is shown below. [Table 56]

[0155] Karl Fischer titration KF titrations for water content determination were performed using a Mettler Toledo C20S coulometric KF titrator equipped with a diaphragm-equipped current generator cell and double platinum pin electrodes. The instrument's detection range is 1 ppm to 5% water. Aquastar™ CombiCoulomat fritless reagents were used in both the anode and cathode compartments. Approximately 0.03 to 0.10 g of sample was dissolved in the anode compartment and titrated until the solution potential dropped below 100 mV. A 1 wt% Hydranal water standard was used for sample verification prior to analysis.

[0156] Microscopic observation Optical microscopy was performed using a Zeiss AxioScope A1 digital imaging microscope equipped with 2.5x, 10x, 20x, and 40x objectives and polarizers. Images were acquired with a built-in Axiocam 105 digital camera and processed using ZEN2 (blue edition) software provided by Zeiss. Optical microscopy was performed using a Hund Wetzlar Wilovert 30 inverted microscope equipped with a MiniVID USB 2.0, 5.1MP digital camera.

[0157] Example 1: Preparation of salts of compound (I) Stock solutions with a concentration of 85 mg / mL were prepared in TFE. Stock solutions of 14 different counterions (e.g., benzenesulfonate, benzoate, phosphate, sulfate, citrate, glucuronate, glutamate, hydrochloride, malate, methanesulfonate, succinate, tartarate, toluenesulfonate, and acetate) were prepared in EtOH. 352 μL (30 mg) of the free base solution was added to each vial. 1.1 and / or 2.2 equivalents of the appropriate counterion stock solution were added to each vial. The vials were left stirring at 45°C for 2 hours, then uncapped and left stirring overnight at 40°C in air to allow evaporation. The vials were then placed under active vacuum at 50°C for 3 hours to dry completely. Approximately 20 volumes (600 μL) of screening solvent were then added to each vial, and the samples were heated to 45°C with stirring (450 rpm). Vials showing significant precipitation or gumming were vortexed frequently to ensure thorough mixing. After 2 hours, the samples were left stirring at room temperature. When a slurry was observed at room temperature, the solids were filtered for characterization.

[0158] Similar experiments were also carried out in EtOAc and IPA:water (9:1 by volume).

[0159] From this salt screen, crystalline salts were observed for benzenesulfonic acid, benzoic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, succinic acid, and phosphoric acid.

[0160] The crystalline salts were characterized and evaluated for potential utility based on melting point, crystallinity, stability upon dry and wet exposure, solubility in water, polymorphism, and counterion acceptability.

[0161] The besylate, benzoate, and phosphate salts were all selected for scale-up for further investigation because they were stable to drying and / or redrying after humidification and all exhibited melting points above 150° C. The sulfate salt was also selected for further investigation.

[0162] In contrast, the solids isolated from the screens using maleic and acetic acids were not selected because they were not confirmed to be salts. Although all yielded stable crystalline patterns throughout the screen, no counterion stoichiometry was observed by NMR for both the acetate and malate salts. The malate salts also had a visibly different appearance after humidification and exhibited low melting points as well as poor water solubility.

[0163] HCl was not chosen because both the observed crystalline pattern and the amorphous solid deliquesced at high humidity, and it had poor physicochemical properties despite its desirable counterion. The mesylate and tosylate salts were not chosen due to their poor counterion acceptance, their low crystallinity, and the deliquescence of the solid (amorphous or crystalline) upon humidification. Sulfuric acid showed two patterns, both of which were stable to humidification, but 9-A exhibited poor thermal behavior and 9-B became a hard, tack-like solid after humidification.

[0164] Example 2: Preparation of amorphous phosphate salt of compound (I) Amorphous material was produced by lyophilization from water and t-BuOH:water (6:4 by volume). Approximately 540 mg of Compound (I) phosphate salt Form A (Example 5) was weighed into a 20 mL scintillation vial, followed by the addition of solvent. Water was added in three 20 mL increments with stirring at room temperature, but no dissolution was achieved. The vial was transferred to a 75°C hot plate, and complete dissolution was achieved within minutes. However, the solution precipitated again after approximately 10 minutes of stirring. The initial mixture ratio of t-BuOH:water was (9:1 by volume), but was readjusted to (6:4 by volume) to achieve dissolution at 75°C. The solution was transferred to a 300 mL beaker, and a total of approximately 500 volumes of t-BuOH:water (6:4 by volume) was added.

[0165] The solution was divided into 20 mL vials, each frozen by immersion in liquid nitrogen for approximately 2 minutes. The solid was transferred to a freeze dryer and kept overnight. XRPD analysis of the solid produced by freeze drying confirmed an amorphous pattern. See Figure 12.

[0166] Example 3: Preparation and characterization of Form G of the phosphate salt of Compound (I) Amorphous Slurry Experiments: Approximately 62 mg of amorphous material (the phosphate salt of Compound (I)) was weighed into a 4 mL vial, and 1 mL of IPA:water (9:1 by volume) was added with stirring at room temperature. A clear solution formed with a gum at the bottom of the vial, which was not broken up by sonication or vortexing. After the sample was left stirring at room temperature for 2 days, it turned into a thick, mobile white slurry. An aliquot was taken, and XRPD analysis confirmed Form G plus Form A. After 9 days on a stir plate at room temperature, XRPD analysis confirmed highly crystalline Form G. Form G showed reduced crystallinity after drying overnight under static vacuum at 50°C, and a sample of highly crystalline G showed reduced crystallinity after 4 days on an XRPD plate at ambient conditions.

[0167] Characterization The simultaneous TGA / DSC thermogram of crystalline pattern G (wet) showed three endothermic events within this temperature range, along with a 30 wt% mass loss between 40 and 140 °C (Figure 2C). A fourth endothermic peak corresponding to melting was observed with an onset temperature of 149.6 °C, which was consistent with the endothermic peak of pattern G obtained in a previous study with an onset temperature of 144.7 °C (Figure 2D).

[0168] DSC and NMR analysis indicate that Form G is a hydrate (mass loss at <100°C by DSC and only 0.3 wt% IPA observed by NMR). KF analysis determined 3.75 wt% water in the sample, supporting 1.3 molar equivalents of water in the sample.

[0169] To test the stability of Form G, it was subjected to 40°C and 75% relative humidity for 7 days. Approximately 10 mg of Form G, the phosphate salt of Compound (I), was weighed into a 4 mL vial and covered with Kimwipe. The vial was placed in a 20 mL vial containing saturated aqueous NaCl. The system was placed on a hot plate at 40°C to create an atmosphere of 75% relative humidity and left for 7 days. The solid was then plated for XRPD analysis. After 1 week, several peak shifts in XRPD were observed, which were consistent with Form O, which does not resolve as well.

[0170] Example 4: Preparation and characterization of Form O, a phosphate salt of Compound (I) Experiments using polymers to promote precipitation were completed using two solvent systems and two different polymers (Table 45). Approximately 30 mg of Form A, the phosphate salt of Compound (I), was weighed into a 2 mL vial, and the solvent was added with stirring at room temperature. For acetone:water (7:3 by volume), 1.4 mL was added to achieve complete dissolution, and for THF:water (7:3 by volume), 400 μL was added. Polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP) polymer were added incrementally, spatula-tip full at a time, while monitoring for precipitation. The solution became more viscous as more polymer was added, turning into a thick, viscous, clear solution; no precipitation was observed in all four samples. The samples were left on a stir plate, and after 8 days, a thick, white slurry formed in the sample prepared in THF:water (7:3 by volume) with PEG. XRPD analysis of the wet cake collected from this sample confirmed Form O. [Table 57]

[0171] Example 5: Preparation and characterization of Form A of the phosphate salt of Compound (I) 5.1. Small-scale preparation 399.4 mg of Compound (I) (free base) was weighed into a 20 mL scintillation vial and a stir bar was added. 10 volumes (4 mL) of TFE was added and the solid was dissolved at 45°C with stirring. 1.1 equivalents (3.5 mL) of phosphoric acid stock solution was added dropwise to the free base solution, and a white precipitate was immediately visible. The solution was stirred at 45°C for 1 hour, then the cap was removed, the temperature was adjusted to 40°C, and the solvent was allowed to evaporate over the weekend. While stirring at 45°C, the white precipitate disappeared, and only a pink rubber remained. The rubber will break up with sonication and vortexing, but the "rubber balls" will quickly regenerate during stirring. The vial was then placed under active vacuum at 50°C for 3 hours. Once removed, the vial contained an off-white solid. 20 volumes of EtOH (8.0 mL) were added to the vial, and an off-white slurry appeared almost immediately. The slurry was allowed to stir at 45° C. for 1 hour and then at room temperature overnight.

[0172] The off-white slurry was sampled for XRPD analysis, which confirmed Form A. The slurry was filtered, washed with 2 x 1.5 volumes (599 μL) of EtOH, and placed under vacuum at 50°C to dry.

[0173] 385.2 mg (81% yield, counterion corrected) of a white solid was collected, and a loss on drying (LOD) of 63% was observed.

[0174] TGA analysis showed a gradual mass loss of 0.3 wt % up to 120° C., followed by a loss of 1.9 wt % up to 210° C. corresponding to melting (FIG. 1B). DSC showed two endothermic events: a small endotherm with an onset temperature of 161.3° C. and a larger endotherm with an onset temperature of 191.8° C. (FIG. 1C).

[0175] The API:CI (counterion) ratio is 1 Residual solvent was found to be 0.45 wt % EtOH, although this was not confirmed by H NMR. Microscopic observation revealed small needles.

[0176] The purity of the phosphate salt was found to be 98.20 a / a% by HPLC.

[0177] 5.2. Large-scale preparation 5.2.1 A solution of Compound (I) (free base) (21.8 kg) in THF (405 kg) at 45-55°C was filtered through a carbon filter. The resulting solution was heated to 60-70°C and distilled to remove 321 kg of THF. To this concentrated solution, 16.5 wt% aqueous phosphoric acid solution (27 kg, 1.1 equivalents) was added along with the mixture at 40-50°C. Wash water (15 kg) was charged, followed by an additional vacuum distillation at 40-50°C to remove approximately 40 kg. To the resulting mixture, acetone (24 kg) at 40-50°C was charged, followed by Compound (I) phosphate seed crystals (26 g). An additional charge of acetone (260 kg) was added, and the mixture was then cooled to 15-25°C. The phosphate salt of Compound (I) was isolated by filtration washing twice with a mixture of acetone / water / THF (47 kg / 6.4 kg / 7.3 kg) to give 26.1 kg, a yield of >99%, and a purity of 99.9%.

[0178] 5.2.2 2-MeTHF (52 mL), acetone (52 mL), and water (70 mL) were charged to a reactor R1 at ambient temperature with stirring, followed by the addition of Compound (I) free base (25 g, 1 equivalent) and concentrated H3PO4 (6.7 g, 76.3 wt% assay, 1.1 equivalents). The mixture in R1 was heated to 50°C and then polish filtered into a separate reactor R2, which was preheated to about 47°C. Acetone (8.7 mL) was added to R2 at about 47°C, followed by the addition of Compound (I) phosphate seed crystals (0.25 g, 1 wt%). The mixture was stirred at about 47°C for 0.5 hours. The remainder of the acetone (450 mL) was added slowly with stirring over 6 hours at the same temperature (240 mL was added over the first 4 hours, followed by the remaining 210 mL over 2 hours). The resulting slurry was cooled to 20-25°C for 18 hours and filtered. The wet cake was washed with a mixture of 2-MeTHF:acetone:water (9:80:11, 38 mL x 2) and then dried under vacuum at 50°C to obtain 27.5 g of Compound (I) phosphate as a solid in 93% yield and 99.94% HPLC purity. XRPD analysis indicates that the resulting Compound (I) phosphate is crystalline Form A.

[0179] The original process for making Compound (I) phosphate Form A was carried out in a solvent mixture of THF / acetone / water. However, as shown in Table A, the residual THF in Compound (I) phosphate Form A prepared using this solvent mixture approached or exceeded the maximum allowable limit (≦720 ppm) per the International Council for Harmonization (ICH) residual solvents guidelines for THF. THF is a Class II solvent considered restricted in pharmaceutical products due to its inherent toxicity, according to the ICH guidelines. [Table 58] Therefore, an improved process for making Compound (I) phosphate Form A was developed using 2-MeTHF instead of THF in the crystallization process. 2-MeTHF is a Class III solvent (a solvent with low toxicity potential) with a maximum allowable limit of 5000 ppm according to ICH guidelines. R&D data show that the newly developed 2-MeTHF process produces good quality Compound (I) phosphate Form A with robust control of residual 2-MeTHF (Table B). [Table 59]

[0180] 5.2. API to Counterion Ratio for Form A, the Phosphate Salt of Compound (I) To determine the API to counterion ratio, known concentrations of both Compound (I) free base and Compound (I) phosphate salt Form A were prepared in volumetric flasks to a concentration of approximately 0.5 mg / mL. These samples were then injected for HPLC analysis. The total area counts under the main API peak were compared for intensity assessment. The intensity was determined to be 88%, which is equivalent to 0.8 molar equivalents of phosphate. Inductively coupled plasma atomic emission spectroscopy (ICP OES) was also completed on Form A. The phosphorus content was determined to be 4.65 wt%, which is in good agreement with the theoretical phosphorus content of 4.94 wt% for monophosphate.

[0181] 5.3. Stability Testing A. Short-term slurry Short-term slurries were performed in 14 solvents at two temperatures according to gravimetric solubility assessment. Vials containing the slurries were centrifuged, and the precipitated solids were collected and filtered for XRPD analysis. A summary of the results is presented in Table 46. Samples prepared in NMP, DMAc, and DMSO at room temperature remained in solution, and no solids were collected. All other 23 samples formed slurries, and Form A was obtained from 21 samples. Form A, the free base (FB-A), plus Form A, the phosphate salt, was obtained in water at 50°C, indicating disproportionation of the phosphate salt. The pattern obtained in TFE at 50°C was from decomposition by-products, as confirmed by HPLC analysis. [Table 60]

[0182] B. Long-term slurry and slow evaporation Slow evaporation and long-term slurry experiments were prepared in 10 different solvents / solvent systems (Table 47). Approximately 8 mg of Compound (I) phosphate salt Form A was weighed into a 2 mL HPLC vial and 1.5 mL of solvent was added with stirring at 35° C.

[0183] The solids in acetone:water (7:3 by volume) and ACN:water (8:2 by volume) were completely dissolved. These samples were prepared for crystallization by slow evaporation. A thin gauge needle was inserted into the vial cap, and the solvent was allowed to evaporate with stirring at 35°C. Samples in neat solvent were dilute slurries, and the solids did not completely dissolve. These samples were used for long-term slurries. To explore the possibility of hydrate formation, water (75 μL) was added to some samples (Table 47), and samples in ACN, THF, and MeOAc were transferred to a 10°C cold plate. After 10 days, the neat solvent samples were filtered and analyzed by XRPD. Form A, the phosphate salt, was obtained in all samples. Form FB-A, the free base, was obtained from two slow evaporation samples. [Table 61]

[0184] C. Crushing Dry and solvent drop milling was carried out using a Wig-L-Bug ball mill with ¼ inch stainless steel balls as the milling media. Approximately 30 mg of solid (Form A, the phosphate salt of Compound (I)) was weighed into each container and 1 volume of solvent was added. Milling was carried out in 3×30 second increments at 3,800 rpm, with the solid being scraped off the container walls to minimize caking between millings. A summary of the resulting patterns is shown in Table 48. XRPD analysis indicated that the solid obtained from the dry milling was amorphous plus traces of Form A. [Table 62]

[0185] Example 6: Preparation and characterization of the besylate salt of compound (I) 6.1. Preparation of Form 1-A, the Besylate Salt 386.5 mg of Compound (I) free base was weighed into a 20 mL scintillation vial and a stir bar was added. 10 volumes (4 mL) of TFE was added and the solid was dissolved at 45°C with stirring. 1.1 equivalents (4.3 mL) of benzenesulfonic acid stock solution was added dropwise to the free base solution, resulting in no visible change. The solution was allowed to stir at 45°C for 1 hour, then the cap was removed, the temperature was adjusted to 40°C, and the solvent was allowed to evaporate over the weekend. The vial was then placed under active vacuum at 50°C for 3 hours. Once removed, the vial contained a thin orange gel / film on the vial walls and no visible solids. 20 volumes of EtOH (7.7 mL) were added to the vial, and an off-white slurry appeared almost immediately. Some orange crust was visible on the walls. The slurry was allowed to stir at 45°C for 1 hour, then at room temperature overnight.

[0186] The off-white slurry was sampled for XRPD analysis, which confirmed the besylate salt, Form 1-A. The slurry was filtered, washed with 2×1.5 volumes (580 μL) of EtOH, and placed under vacuum at 50° C. to dry. 98.4 mg (20% yield, counterion corrected) of a white solid was collected, and an LOD (loss on drying) of 71% was observed.

[0187] TGA showed a mass loss of 0.9 wt % up to 120° C. and a loss of 0.8 wt % up to 200° C. (FIG. 4B). Only one endothermic event was observed in the DSC thermogram with an onset temperature of 189.4° C. (FIG. 4C). The stoichiometry was 1 H NMR confirmed an API:CI ratio of approximately 1:2. Exact stoichiometry is difficult to obtain due to several overlapping peaks. Residual solvent was found to be 0.17 wt% EtOH.

[0188] The purity for the besylate scale-up was found to be 93.12 a / a% by HPLC.

[0189] 6.2. Preparation of Form 1-B, the Besylate Salt Besylate Form 1-B was formed after besylate Form 1-A was subjected to humidity testing and re-dried.

[0190] Example 7: Preparation and characterization of the benzoate salt of compound (I) 7.1. Preparation of Benzoate Salt Form 2-A 389.8 mg of Compound (I) free base was weighed into a 20 mL scintillation vial and a stir bar was added. 10 volumes (4 mL) of TFE was added and the solid was dissolved at 45°C with stirring. 1.1 equivalents (3.5 mL) of benzoic acid stock solution was added dropwise to the free base solution, resulting in no visible change. The solution was allowed to stir at 45°C for 1 hour, then the cap was removed, the temperature was adjusted to 40°C, and the solvent was allowed to evaporate over the weekend. The vial was then placed under active vacuum at 50°C for 3 hours. Once removed, the vial contained an off-white solid as well as an orange crust on the vial walls. 20 volumes of EtOAc (7.8 mL) were added to the vial, and an off-white slurry appeared almost immediately. Some orange crust was visible on the walls. The slurry was allowed to stir at 45°C for 1 hour, then at room temperature overnight.

[0191] The off-white slurry was sampled for XRPD analysis, which confirmed the benzoate salt, Form 2-A. The slurry was filtered, washed with 2×1.5 volumes (585 μL) of EtOAc, and placed under vacuum at 50° C. to dry. 347.1 mg (72% yield, counterion corrected) of white solid was collected, and an LOD of 54.7% was observed.

[0192] TGA analysis showed a mass loss of 0.2 wt% up to 120°C, followed by a loss of 5.4 wt% up to 200°C (accompanied by melting) (Figure 6B). The DSC thermogram showed two endotherms at 171.3°C and 180.8°C (Figure 6C). The stoichiometry was 1 H NMR confirmed 1:1 API:CI, and residual solvent was found to be 0.83 wt% EtOAc. Microscopic examination revealed small rods and needles.

[0193] The purity of the benzoate salt was found to be 96.53 a / a% by HPLC.

[0194] 7.2. Preparation of Benzoate Salt Form 2-B Benzoate Form 2-B was formed after benzoate Form 2-A was subjected to humidity testing and re-dried.

[0195] Example 8: Preparation and characterization of the sulfate salt of compound (I) A sulfuric acid stock solution was prepared in TFE with a concentration of 85 mg / mL in IPA:water (9:1 by volume). 352 μL (30 mg) of the free base solution was added to the vial. 1.1 equivalents of the sulfuric acid stock solution was added to the vial. The vial was left stirring at 45°C for 2 hours, then uncapped and left stirring overnight at 40°C in air to allow evaporation. The vial was then placed under active vacuum at 50°C for 3 hours to dry completely. Approximately 20 volumes (600 μL) of screening solvent was then added to the vial, and the sample was heated to 45°C with stirring (450 rpm). The sample was left stirring at room temperature. The solid was filtered for characterization. XRPD analysis indicates that the sulfate salt, Form 9-A, was formed.

[0196] Example 9: Amorphous Compound (I) Free Base The solubility of Compound (I) free base was tested in various solvents (Table 49). [Table 63]

[0197] The solubility of Compound (I) free base was relatively good in acetonitrile (ACN):water (7:3 by volume), tert-butanol (t-BuOH), and t-BuOH:water (9:1 by volume). These solutions were filtered by syringe filtration (Samples 83-1 and 83-2) before being used for freeze-drying experiments. The samples were first frozen in liquid nitrogen and then placed in the vacuum system of a freeze-dryer (0.045 mbar, collector temperature -89 °C). Vacuum drying at room temperature was carried out overnight, and then the samples were removed and prepared for XRPD analysis. The samples were stored in paraffin-wrapped vials and left on the bench at room temperature. The XRPD (see Figure 14) was recorded the next day.

[0198] Example 10: Preparation of Compound (I) Free Base Synthesis of (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)ethanol [ka] Synthesis of 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine: [ka] A mixture of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol (10.0 g, 46.7 mmol), phosphorus oxychloride (13.0 mL, 140 mmol), and triethylamine (13.0 mL, 93.5 mmol) in toluene (100 mL) was stirred at 120 °C for 18 h. The reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:10 to 1:2 EtOAc / petroleum ether, to give the title compound (9.4 g, 87% yield) as a pale yellow solid. MS (ES+) CHBrClN requires: 231, found: 232, 234 [M+H] + .

[0199] Synthesis of (S)-1-(2-(4-(6-bromopyrrolo[1,2-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethanamine: [ka] A mixture of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine hydrochloride (2.00 g, 6.63 mmol), 6-bromo-4-chloropyrrolo[1,2-f][1,2,4]triazine (2.31 g, 9.94 mmol), and triethylamine (2.00 g, 19.8 mmol) in dioxane (20 mL) was stirred at room temperature for 2 hours. LC-MS showed complete conversion of the reaction. The mixture was purified by flash column chromatography (DCM / MeOH=20 / 1) to give the title compound (1.51 g, 45% yield) as a white solid. MS (ES+) C 22 H 22 BrFN8 required value: 496, actual value: 480 [M-16] + .

[0200] Synthesis of (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)ethanol (compound (I)): [ka] A mixture of (S)-1-(2-(4-(6-bromopyrrolo[1,2-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethanamine (500 mg, 1.00 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (285 mg, 1.20 mmol), Pd(dppf)Cl (219 mg, 300 μmol), and NaCO (317 mg, 3.00 mmol) in dioxane / water (20 mL / 2 mL) was stirred at 100 °C under N overnight. LC-MS showed complete conversion of the reaction. The mixture was purified by flash column chromatography (DCM / MeOH=15 / 1) and preparative HPLC (mobile phase: A=water (0.1% NH4HCO3), B=acetonitrile; gradient: B=15%-95% in 18 min; column: Xtimate 10 um 150A 21.2×250 mm) to give the title compound (154.0 mg, 29% yield) as a white solid. MS (ES+) C 27 H 29 FN 10 Required value: 528, Measured value: 529 [M+H] + . 1 H-NMR (400 MHz, 6d-DMSO) δ ppm 8.40 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.49-7.44 (m, 2H), 7.24 (s, 1H), 7.14-7.07 (m, 2H), 4.95 (t, 1H, J = 5.2 Hz), 4.16-4.12 (m, 2H), 4.11-4.07 (m, 4H), 3.92-3.88 (m, 4H), 3.77-3.72 (m, 2H), 2.44 (br. S., 2H), 1.73 (s, 3H).

[0201] The XRPD spectrum (Figure 15) and peaks (Table 50) of the obtained product are shown below. [Table 64]

[0202] Example 11: Interconversion between free base crystalline forms The same crystalline form of free base Compound (I) may contain various amounts of water (i.e., channel hydrates) and thus be characterized as different subforms, such as Form FB-A-0 (monohydrate), FB-A-1 (metastable hydrate), and FB-A-2 (dehydrate). Crystalline forms FB-A, FB-A-1, and FB-A-2 can be interconverted between each other. For example, Form FB-A-1 can be obtained from Form FB-A by slurrying in MeOH or EtOH at 50°C, or by slurrying in DCM:MeOH (40:60 by volume) and rapidly cooling. Form FB-A-1 can be converted to Form FB-A at 40°C under humidified conditions at 75% RH.

[0203] Form FB-A-2 can be obtained from Form FB-A-0 by drying under vacuum at 50° C. for 3 days. The sample was purged with nitrogen upon removal from the oven, and the sample was immediately covered in an airtight holder and subjected to XRPD analysis.

[0204] Example 12: Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study to evaluate the safety, tolerability, and pharmacokinetics of Compound (I) Parts 1 and 2 were randomized, double-blind, placebo-controlled studies of oral administration of Compound (I) at the SAD (Part 1) and MAD (Part 2) in healthy adult subjects. Compound (I) was administered as the monophosphate salt. Subjects were screened within 28 days prior to the first dose. Subjects participated in only one cohort in only one study part.

[0205] Part 1 (SAD): Six cohorts of eight subjects each (six active and two placebo) were evaluated. Cohorts of subjects aged ≥18 years received either an oral placebo (n=2 / cohort) or a single oral dose of 15, 25, 50, 100, or 200 mg of Compound (I) (n=6 / cohort) in the fasted state. The first cohort (Cohort S1) included a sentinel group (one active and one placebo), which was dosed at least 24 hours before the remaining six subjects (five active and one placebo). Dosing of the remaining six subjects in Cohort S1 occurred following safety evaluation of the sentinel group.

[0206] Plasma samples for pharmacokinetic (PK) evaluation were collected pre-dose and up to 96 hours after administration of Compound (I) or placebo. Blood samples for measuring pharmacodynamic (PD) biomarker (tryptase) concentrations were collected pre-dose on Day -1, Day 2, and Day 5. Cardiac dynamics ECG sampling was collected pre-dose and up to 24 hours after Compound (I) administration.

[0207] Once the Safety Review Committee (SRC) determined that sufficient safety and tolerability had been demonstrated, dose escalation to the next cohort was performed.

[0208] Part 2 (MAD): Four cohorts of eight subjects each (six active and two placebo) were evaluated. In each cohort, subjects received daily oral doses of 25, 50, or 100 mg of Compound (I) or placebo (3:1 ratio) for 10 consecutive days in the fasted state.

[0209] Plasma samples for PK assessment were collected pre-dose on days 1-10. Plasma samples for PK assessment were also collected up to 24 hours post-dose on day 1 and up to 96 hours post-dose on day 10. Blood samples for measuring PD biomarker (tryptase) concentrations were collected pre-dose on day 1 and pre-dose on days 2, 5, and 9. Cardiac dynamics ECG sampling was collected pre-dose and up to 24 hours post-dose of Compound (I) on days 1 and 10. Safety was assessed according to the incidence and severity of adverse events in recipients of Compound (I) compared to placebo.

[0210] Compound (I) was well tolerated across the five Compound (I) SAD cohorts and three MAD cohorts. Only Grade 1 adverse events, mostly non-drug-related, were reported, including abdominal pain, decreased appetite, fatigue, headache, and nausea. No serious AEs were reported, and there were no clinically significant findings in reported laboratory or vital sign parameters. After administration of a single dose of Compound (I), the median Tmax ranged from 1.5 to 6 hours post-dose. The mean half-life (t1 / 2) of Compound (I) ranged from 20 to 28 hours, indicating steady-state is expected to be reached by day 7, thus supporting once-daily dosing. After 10 days of repeated oral administration of 25 to 100 mg of Compound (I), the geometric mean AUC accumulation ratios ranged from 1.6 to 1.8. The geometric mean Vz / F ranged from 753 to 973 L, indicating extensive tissue distribution. Overall, a dose-proportional increase in systemic exposure to Compound (I) was observed across the SAD and MAD cohorts. The pharmacokinetics of Compound (I) were linear across the dose range in the SAD and MAD cohorts.

[0211] Example 13: A randomized, double-blind, placebo-controlled Phase 2 / 3 study of Form A of the phosphate salt of Compound (I) (referred to in this Example 13 as "Compound (I)") in painless systemic mastocytosis This is a randomized, double-blind, placebo-controlled Phase 2 / 3 study comparing the efficacy and safety of Compound (I) plus best supportive care (BSC) with placebo plus BSC in patients with ISM whose symptoms are not adequately controlled with BSC. Part 1 will identify the recommended dose (RD) of Compound (I) in patients with ISM who have an ISM-SAF TSS of ≥ 28. Part 2 will randomize patients with ISM, regardless of their ISM-SAF TSS, to receive Compound (I) plus BSC or a matching placebo plus BSC for the RD identified in Part 1. In Part M, patients with mMCAS will receive Compound (I) plus BSC for their RD under open-label conditions. In Part 3, patients who complete Part 1 or Part 2 of the study will participate in a long-term extension study in which they will receive RD plus BSC under open-label conditions.

[0212] Screening (all parts) After providing written informed consent, patients will be assessed for eligibility during a screening period.

[0213] Eligibility for the TSS for Part 1 will be determined by averaging the daily ISM-SAF over a 14-day period. Patients who meet the symptom severity threshold will continue to complete the ISM-SAF daily without interruption throughout the screening period and, if otherwise deemed eligible, throughout the study participation period. After symptom eligibility by the ISM-SAF in Part 1 is confirmed, the remaining screening assessments will begin.

[0214] Patients in Part 2 will complete the ISM-SAF daily over the screening period to determine a baseline score, but inclusion in the study will not depend on a specific TSS. Enrollment will be stratified by TSS score (<28 and >28), and a minimum number of patients with a TSS >28 will be required.

[0215] Screening procedures for Parts 1, 2, and M include: BM biopsy (archived or fresh specimen obtained within the past 12 weeks; BM biopsy within the last 12 months is acceptable for mMCAS patients) and lesional and non-lesional skin biopsies (in patients in Part 1 or Part 2 with cutaneous mastocytosis). BM and skin biopsies are performed and sent to a central pathology laboratory for confirmation of the ISM or mMCAS diagnosis and quantification of MC. Patients with cutaneous mastocytosis may elect to have their skin photographed. Additional procedures include magnetic resonance imaging (MRI) or computed tomography scan of the brain, bone densitometry, serum tryptase, testing for the KIT D816V mutation, allele load, routine laboratory tests, ECG, and physical examination. Confirmation of the ISM or mMCAS diagnosis by a central laboratory is required.

[0216] Randomization in Parts 1 and 2 will occur following screening and once patients are deemed eligible to participate.

[0217] In Part 1 of the study, approximately 40 evaluable ISM patients with a TSS of ≥ 28 will be equally randomized (1:1:1:1 ratio) to one of three doses of Compound (I) + BSC or placebo + BSC. Three dose levels (25 mg, 50 mg, or 100 mg) of Compound (I) + BSC and placebo + BSC will be tested in parallel. Compound (I) will be administered orally once daily (QD) continuously. Patients will be evaluated weekly for safety, laboratory monitoring, and quality of life (QoL) assessments over the first 4 weeks. Pharmacokinetic sampling will be performed in all patients. Pharmacokinetic data will be unblinded after completion of central PK collection (C1D1 and C1D15) for all patients. ISM-SAF will be completed daily. After completion of 12 weeks of treatment, BM and skin biopsies will be repeated for MC quantification by a central pathology laboratory, and skin photography (optional) may be performed in patients with baseline cutaneous mastocytosis. The RD will be determined based on efficacy, safety, and PK data at each dose level. The primary efficacy criterion for selection of the RD is the dose of Compound (I) that results in the greatest reduction in TSS as assessed using the ISM-SAF at Week 13 compared to baseline. Other efficacy measures (e.g., change in serum tryptase) will also be taken into consideration. Once the Week 13 assessment is complete, patients will continue their assigned treatment and dose until the RD is determined, at which point all patients in Part 1 will be unblinded and transitioned to Part 3, where they will receive Compound (I) at their RD in an open-label manner.

[0218] Part 2 of the study will enroll up to 303 ISM patients (at least 204 evaluable patients with a TSS of ≥ 28 and up to 99 patients with a TSS of < 28). Patients will be randomized in a 2:1 ratio to receive either Compound (I) + BSC or matching placebo + BSC, respectively. Randomization will be stratified based on TSS score (< 28 and > 28) and centrally measured serum tryptase levels at screening (< 20 ng / mL vs. ≥ 20 ng / mL). Furthermore, enrollment of patients with serum tryptase < 20 ng / mL will be capped at approximately 20% for patients with a TSS of ≥ 28 and approximately 20% for patients with a TSS of < 28.

[0219] Compound (I) and placebo will be administered orally once daily continuously. Patients will be evaluated every 4 weeks until week 25 for safety, clinical laboratory monitoring, and QoL assessments. Sparse PK sampling will be performed in all patients. Skin photographs will be taken every 12 weeks for patients with cutaneous mastocytosis who so choose. ISM-SAF will be completed daily.

[0220] After completing 24 weeks of treatment, ISM-SAF, BM, and skin biopsies will be repeated for mast cell (MC) quantification by a central pathology laboratory, and skin photography (optional) may be taken in patients with baseline cutaneous mastocytosis. Each patient who completes the Week 25 assessment will enter Part 3, a long-term extension study, and will receive Compound (I) at RD once daily in an open-label fashion. The Week 25 assessment is the baseline for Part 3. After all patients in Part 2 have entered Part 3, all treatment assignments in Part 2 will be unblinded. At this point, the primary endpoint, the proportion of patients with a ≥ 30% reduction in TSS from baseline to Week 25, as well as other efficacy endpoints, will be analyzed.

[0221] After all patients in Part 1 have completed Part 1 and their RD has been determined, or when each patient in Part 2 completes the Week 25 study assessment, patients will transition to Part 3. All patients will receive open-label treatment with Compound (I) for their RD.

[0222] In Part 3, patients in Part 1 receiving Compound (I) will attend study visits every 4 weeks until Week 25, then every 8 weeks until Week 49. After Week 49, patients will attend visits every 12 weeks for a total treatment duration of up to 5 years, including Part 1 or Part 2 as appropriate. Patients in Part 1 receiving placebo will attend weekly visits until Week 5.

[0223] In Part 3, patients transitioning from Part 2 will visit weekly until week 5, then follow the same schedule as Part 1 patients.

[0224] For patients in Part 1 and Part 2, the ISM-SAF will be completed daily, and QoL assessments will be conducted at study visits until Week 49 of Part 3 or end of treatment (EOT), whichever occurs first. In patients who had or developed cutaneous mastocytosis during Part 1 or Part 2, skin photographs (optional) may be taken at baseline in Part 3 (if not obtained within the past 4 weeks in Part 1 or Part 2) and at other time points. One year after the Week 13 biopsy in Part 1 or one year after the Week 25 biopsy in Part 2, optional BM and skin biopsies will be repeated for MC quantification by a central pathology laboratory. For patients randomized to placebo in Part 1 or Part 2, the completion of Part 1 or Part 2 study assessments, including BM and skin biopsies, will serve as the baseline assessment for Part 3.

[0225] In Part M of the study, approximately 20 patients with mMCAS will receive Compound (I) (once daily) plus BSC in an open-label, single-arm RD. Dose, formulation, and administration will be the same as described for Part 2. This part does not include a placebo group. After completion of 24 weeks of treatment, BM biopsies will be repeated for MC quantification by a central pathology laboratory. Patients will proceed to the long-term follow-up portion of Part M.

Claims

1. The following formula: 【Chemistry 1】 wherein the molar ratio between compound (I) and phosphoric acid is 1:1, the molar ratio between compound (I) and benzenesulfonic acid is 2:1, the molar ratio between compound (I) and sulfuric acid is 1:1, and the molar ratio between compound (I) and benzoic acid is 1:

1.

2. The salt of claim 1 , wherein the salt is unsolvated.

3. The salt of claim 1 , wherein the salt is a phosphate salt.

4. 4. The phosphate salt of claim 3, wherein the salt is a crystalline salt of Form A characterized by an X-ray powder diffraction pattern comprising peaks at 4.6°, 11.8°, 13.7°, 18.3°, and 19.8°±0.2 in 2θ.

5. 4. The phosphate salt of claim 3, wherein the salt is Form G of a crystalline salt characterized by an X-ray powder diffraction pattern comprising peaks at 4.1°, 4.4°, 7.4°, 15.6°, and 23.0°±0.2 in degrees 2θ.

6. 4. The phosphate salt of claim 3, wherein the salt is a crystalline salt of Form O, characterized by an X-ray powder diffraction pattern comprising peaks at 4.2°, 15.2°, 21.6°, 21.9°, and 22.6°±0.2 in 2θ.

7. The salt of claim 1 , wherein the salt is a besylate salt.

8. 8. The besylate salt of claim 7, wherein the salt is a crystalline salt of Form 1-A characterized by an X-ray powder diffraction pattern containing peaks at 5.7°, 7.1°, 9.7°, 15.4°, and 24.8°±0.2 in 2θ.

9. 8. The besylate salt of claim 7, wherein the salt is a crystalline salt of Form 1-B characterized by an X-ray powder diffraction pattern containing peaks at 5.5°, 10.4°, 14.0°, and 16.3°±0.2 in 2θ.

10. The salt of claim 1 , wherein the salt is a sulfate salt.

11. 11. The sulfate salt of claim 10, wherein the salt is Form 9-A crystalline salt characterized by an X-ray powder diffraction pattern containing peaks at 9.0°, 10.4°, 13.6°, 18.1°, and 21.0°±0.2 in 2θ.

12. The salt of claim 1 , wherein the salt is a benzoate salt.

13. 13. The benzoate salt of claim 12, wherein the salt is a crystalline salt of Form 2-A characterized by an X-ray powder diffraction pattern containing peaks at 4.1°, 10.6°, 16.8°, 18.1°, and 22.7°±0.2 in 2θ.

14. 13. The benzoate salt of claim 12, wherein the salt is a crystalline salt of Form 2-B characterized by an X-ray powder diffraction pattern containing peaks at 5.8°, 9.7°, 15.4°, and 17.8°±0.2 in 2θ.

15. A compound (I) in amorphous form, represented by the following formula: 【Chemistry 2】 。

16. A pharmaceutical composition comprising a salt of compound (I) according to any one of claims 1 to 14 or the amorphous form of compound (I) according to claim 15, and a pharma- ceutically acceptable carrier or diluent.

17. 17. A pharmaceutical composition for treating a disease or condition in a patient in need thereof, the pharmaceutical composition comprising a salt of compound (I) according to any one of claims 1 to 14, an amorphous form of compound (I) according to claim 15, or a pharmaceutical composition according to claim 16, wherein the disease or condition is selected from systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic, and leukemia.

18. A pharmaceutical composition comprising compound (I) for use in a method for treating indolent systemic mastocytosis (ISM) or monoclonal mast cell activation syndrome (mMCAS), the method comprising administering to a patient in need thereof an amount of 15 mg to 200 mg of compound (I). 【Chemistry 3】 Or the pharmaceutical composition comprising orally administering 15 mg to 200 mg of compound (I) or an equivalent amount of a pharma- ceutically acceptable salt thereof once a day.

19. Compound (I) of Form A according to claim 4: 【Chemistry 4】 1. A process for the preparation of a crystalline phosphate salt of compound (I), comprising forming the phosphate salt of compound (I) with phosphoric acid in an organic solvent mixture comprising 2-MeTHF / acetone / water.

20. 20. The process of claim 19, further comprising crystallizing Form A of the phosphate salt of Compound (I) by adding acetone.

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